Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by Aspergillus induced hypersensitivity that occurs in immunocompetent but susceptible patients with asthma and/or cystic fibrosis (CF). In children, ABPA remains mostly undiagnosed, resulting in one of the most common causes of poorly controlled asthma and highly significant morbidity in children with CF. Currently, no specific diagnostic criteria of ABPA for children are available. Corticosteroids and itraconazole are the mainstays of therapy, althoughthere is a lack of randomized clinical trials regarding their usefulness for ABPA in children. Several monoclonal antibodies, such asomalizumab and mepolizumab, may be potential therapies for refractory ABPA in pediatric patients; however, further data are required to clarify the optimal dose and duration of therapy as a routine treatment approach.

Autoimmune neutropenia of infancy (AIN) is a relatively frequent cause of neutropenia in children. The disease is caused by antibodies recognizing membrane antigens of neutrophils, mostly located on immunoglobulin G (IgG) Fc receptor type 3b (FcγIIIb receptor). In this study, we investigated the possible association of human neutrophil antigens (HNA), human leukocyte antigen (HLA)-DR and HLA-DQ alleles with AIN and the association of these genotypes with the presence of anti-HNA-1a autoantibodies. Eighty AIN cases with a median age of 13.5 months were included in this study. Controls were healthy unrelated Danish blood donors. Anti-HNA-1a autoantibodies were detected using a flow cytometric granulocyte immunofluorescence test (Flow-GIFT). Molecular determination of HNA genotypes was determined using real-time polymerase chain reaction (q-PCR). High-resolution HLA-DR and HLA-DQB1 were determined by next-generation sequencing. Antibodies against HNA-1a were detected in 51% (n=41) of AIN patients, and anti-HNA-1b was detected in 3% (n=2) of cases. FCGR3B*01+,*02-,*03- was more common (odds ratio, 6.70; p < 0.0001), and FCGR3B*01-,*02+,*03- was less common (odds ratio, 0.30; p < 0.0001) among AIN cases. HNA-1a antibodies were significantly more frequent among AIN cases with the FCGR3B*01+,*02-,*03-genotype (odds ratio, 3.86; p < 0.007). The HLA-DR*14 and HLA-DQB1*05:03 alleles were significantly more common (odds ratio, 7.44; p < 0.0001 and odds ratio, 2.50; p < 0.0001, respectively) in AIN patients. In conclusion the HLA haplotype HLA-DR*14- DQB1*05:03 is associated with Danish AIN cases. Among Danish AIN patients, anti-HNA-1a is the most common autoantibody, and the antibody is more common in cases with the FCGR3B*01-,*02+,*03- genotype.

Background: recent epidemiological studies state that a high dose of folic acid status during pregnancy increases the risk of asthma, wheezing, and respiratory disease in childhood. As potential biological mechanism, folate acid can modify inflammation and immune susceptibility of offspring with some epigenetic differentiation, including DNA methylation. This study evaluated the association between maternal folate levels during pregnancy with childhood wheeze, and whether DNA methylation differentiation of children in genes is related to wheezing or not. Methods: the cohort comprised 6651 mother–child pairs who were evaluated for an association between maternal folate level during pregnancy and childhood wheeze at 1, 2, 4, and 7 years age, which were assessed by the International Study of Asthma and Allergies in Childhood questionnaire. Results: the median of maternal serum was 16.76 nmol/l, assayed by chemiluminescent immunoassay. We found significantly increased adjusted odds ratios of childhood wheeze at 2 years age according to maternal folate levels, compared with lowest folate quartile (odds ratio [95% confidence interval] = highest; 1.27 [1.03, 1.56], and second; 1.27 [1.05, 1.55]), however, no changes were observed at 1, 4, and 7 years age. In a case-control study of childhood wheeze due to DNA methylation at 7 years age, no association of maternal folate levels with DNA methylation was observed. Conclusion: our result proposes that the negative effect of maternal folate on an infant’s wheeze did not remain until 7 years of age and no association with maternal folate levels and DNA methylation (at the same age) was observed.

To the Editor, For the EU funded project PERMEABLE (PERsonalized MEdicine Approach for Asthma and Allergy Biologicals SeLEction), which addresses the availability of and access to advanced therapy of asthma in children across Europe, we performed a survey including 37 major pediatric asthma and allergy centers between September 2019 and July 2020. In total, the centers contributing to the survey treated approximately 1.000 young patients with severe asthma in 25 major European countries and Turkey with biologicals. In the light of the Corona Pandemic, we extended our survey asking the responsible clinicians if they experienced a SARS-CoV-2 infection in any of the children they are caring for. The questions pertaining to Corona infections were asked between March and July 2020.Given the prevalence of SARS-CoV-2 infections in the general population and in children, one would expect that at least 1% of the patients would be affected (1). In fact, none of the centers was aware of any symptomatic COVID-19 case in their patient populations or any positive SARS-CoV-2 tests.This leads to the conclusion, that either SARS-CoV-2 infections have a mild or even asymptomatic course also in children with severe asthma or that children with severe asthma (and their parents) were extremely successful in avoiding SARS-CoV-2 infections. Thus, we investigated by structured interview, how centers in those 26 countries had instructed their patients to avoid COVID-19. Interestingly, only 4 European countries (UK, Ireland, Portugal and Malta) had a strict, so called shielding policy in place which followed a principle of maximal segregation of severe asthmatics from the rest of the population: not leaving the house at all, not attending school even when they reopened, wearing face masks also at home, and social distancing even with family members. All other countries followed the principle of continuing or even enforcing asthma treatment in patients and advising to follow the same Corona rules as the general population.Both strategies led to the same result: An absence of COVID-19 cases in children with severe asthma. We conclude from this observation, that shielding is not necessary in children with severe asthma as they and their families are perfectly able to avoid Corona infections. The harm done to children by enforcing seclusion, separation and stigmatization needs to be acknowledged. Deprivation of school, social contact and friends weights heavy on children and the absence of any COVID-19 cases in major European centers for severe asthma in children does not justify a policy of compulsory shielding of children with severe asthma, neither in the first nor in any further Corona wave.Michael Kabesch, M.D.University Children’s Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany.Member of the Research and Development Campus Regensburg (WECARE) at the Hospital St. Hedwig of the Order of St. John, Regensburg, Germany.ReferencesStringhini S, Wisniak A, Piumatti G, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study [published online ahead of print, 2020 Jun 11]. Lancet . 2020;S0140-6736(20)31304-0.

Background: There is paucity of literature on long term follow-up of patients with Hereditary angioedema (HAE) from developing countries. Objective: This study was carried out to analyse the clinical manifestations, laboratory features and genetic profile of 32 patients (21 male and 11 female) from 23 families diagnosed with HAE between January 1996 and December 2019. Methods: Data were retrieved from medical records of the Paediatric Immunodeficiency Clinic, Post Graduate Institute of Medical Education and Research, Chandigarh, India. Results: Median age at onset of symptoms was 6.25 years (range 1–25 years) and median age at diagnosis was 12 years (range 2-43 years). Serum complement C4 level was decreased in all patients. All patients had low C1- esterase inhibitor (C1-INH) quantitative level (type 1 HAE). SERPING1 gene sequencing could be carried out in 20 families. Of these, 11 were identified to have a pathogenic disease-causing variant in the SERPING1 gene. While 2 of these families had a previously reported mutation, remaining 9 families had novel pathogenic variants in SERPING1 gene. Because of non-availability of C1-INH therapy in India, all patients were given long term prophylaxis (attenuated androgens or tranexamic acid or a combination of the 2). Life-threatening episodes of laryngeal oedema were managed with fresh frozen plasma infusions. Only one disease related mortality was reported in the entire cohort. Conclusions: We report largest single centre cohort of patients with HAE from India. Attenuated androgens, fibrinolytic agents and fresh frozen plasma may be effectively used for management of HAE in resource limited settings.

The prevalence, heterogeneity and severity of type 2 inflammatory diseases, including asthma and atopic dermatitis, continue to rise, especially in children and adolescents. Type 2 inflammation is mediated by both the innate and adaptive immune cells and sustained by a specific subset of cytokines, such as interleukin(IL)‐4, IL‐5,IL‐13, and IgE. IL-4 and IL-13 are considered signature type 2 cytokines, as they both have a pivotal role in many of the pathobiological changes featured in asthma and atopic dermatitis. Several biologics targeting IL-4, IL-5, and IL-13, as well as IgE, have been proposed to treat severe allergic disease in the pediatric population with promising results. A better definition of type 2 inflammatory pathways is essential to implement targeted therapeutic strategies.

Anaphylaxis in children is a potential acute life-threatening systemic hypersensitivity reaction. Anaphylaxis fatality rate is estimated to be 0.65% to 2%. Food is the main anaphylaxis trigger in children, notably cow’s milk, peanuts and tree nuts. Mucocutaneous manifestations are observed in more than 90% of cases, but it is not essential for diagnosis. Deaths are rather secondary to the laryngeal edema, observed in 40-50% of cases. Personal history of asthma, allergy to particular foods such as peanuts and tree nuts, and adolescence are known risk factors for anaphylaxis and more severe reactions. Epinephrine (adrenaline) is the medication of choice for the first-aid treatment of anaphylaxis. However, adrenaline auto-injectors (AAIs) are commercially available in only 32% of world countries. There are still considerable unmet needs in the field of anaphylaxis in children. Therefore, the Montpellier WHO Collaborating Centre aims to start the global actions plan applied to anaphylaxis.

Background: We previously reported that the specific IgE levels to αs1-casein (CN) and β-CN in patients with cow’s milk allergy decreased with similar dynamics during oral immunotherapy. Therefore, we hypothesized that αs1- and β-CN have strong cross-reactivity among CN components, despite the low similarity in the full-length amino acid sequences. Methods: The αs1-, β-, and κ-CN were purified from commercial cow’s milk. We recruited 39 patients with cow’s milk allergy and the serum IgE levels for each CN component were measured by enzyme-linked immunosorbent assay (ELISA). Cross-reactivity between CN components was investigated by competitive ELISA against αs1-CN. Sequence homology between CN components at the peptide level was calculated using in silico analysis and quantified by the Property Distance (PD) value. Results: The αs1-CN-specific IgE levels exhibited a strong positive correlation with the β-CN-specific IgE (r = 0.945, P < 0.001). Complete competition was observed by β-CN against αs1-CN, suggesting the presence of common epitopes between them. In silico analysis detected 24 peptide sets with PD values lower than 10 between αs1- and β-CN, and 14 sets between αs1- and κ-CN. The amino acid sequences of αs1- (E61-E70) and β-CN (I12-E21) that showed the lowest PD value (5.30) were present in the characteristic sequence known as casein phosphopeptide (CPP). Conclusion: We detected strong cross-reactivity between CN components. Furthermore, we found highly homologous sequences in the CPP region, which contains a core sequence of “SSSEE” with phosphorylated serine residues.

Background The association between dyslipidemia and atopic dermatitis in children is unclear. This study investigated the association between dyslipidemia and atopic dermatitis in children by analysis of disease onset, risk factors, and disease severity. Methods Subset I examined 7 year-old children in elementary school (n = 248) and Subset II was a retrospective long-term follow-up hospital based-study (n = 52,725) conducted from 1986 to 2016 that used propensity score matching. In the Subset I Study, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) were determined, and the severity of atopic dermatitis was determined using SCORing Atopic Dermatitis (SCORAD). In the Subset II Study, the time of atopic dermatitis onset was determined for asymptomatic subjects whose TC levels were below or above 170 mg/dL. Results Our Subset I Study indicated that children with atopic dermatitis (n = 69, 27.8%) had significantly higher levels of TC and TG, and that disease severity had significant associations with high levels of TC and TG, and a low level of HDL-C. Our Subset II Study (1,722 with high TC and 6,735 with normal TC after propensity score matching) indicated the high TC group had a greater hazard ratio (HR) for the onset of atopic dermatitis (consensus-based HR: 2.47; 95% CI: 1.23, 5.06, P = 0.012) during 5 years. Conclusion An abnormal blood lipid profile in children is associated with the presence and severity of atopic dermatitis. The risk of atopic dermatitis onset was significantly greater with high levels of TC.

Background: Previous studies have investigated the natural course of cow’s milk protein allergy (CMPA) and development of atopic diseases into adolescence. Studies with long term follow-up into adulthood are lacking. The aim of this study was to investigate 1) the natural course of CMPA in a 1-year birth cohort of Danish children from birth until 15 and 26 years of age and 2) the development of atopic diseases in a group of children with CMPA (group A) compared to a random sample of 276 children from the same birth cohort (group B). 
Methods: A birth cohort of 1,749 newborns, was investigated prospectively for the development of CMPA and atopic diseases. During the first year of life and at 18 months and 3, 5, 10, 15, and 26 years of age, questionnaire based interviews, physical examination, skin prick tests and specific IgE testing, and from 10 years also spirometry, were carried out. 
Results: 39 (2,2%) were diagnosed with CMPA. The recovery rate was 87%, 92% and 97% at 3, 5 and 26 years of age. Compared to group B, group A had significantly (p < 0,05) higher prevalence of asthma and rhinoconjunctivitis at 15 years of age and at 26 years of age, group A had significantly higher prevalence of asthma and atopic dermatitis. The follow-up rate was 85% (A) and 70% (B). 
Conclusion: CMPA has a good prognosis regarding recovery rate. CMPA and sensitization in early childhood predict sensitization and persistence of allergic diseases into adulthood.

Food allergy is increasing in prevalence, affecting up to 10% of children in developed countries. Food allergy can significantly affect the quality of life and well-being of patients and their families; therefore, an accurate diagnosis is of extreme importance. Some food allergies can spontaneously resolve in 50-60% of cow’s milk and egg allergic, 20% of peanut allergic and 9% of tree nut allergic children by school age. For that reason, food allergic status should be monitored over time to determine when to reintroduce the food back into the child’s diet. The gold-standard to confirm the diagnosis and the resolution of food allergy is an oral food challenge; however, this involves a risk of causing an acute allergic reaction and requires clinical experience and resources to treat allergic reactions of any degree of severity. In the clinical setting, biomarkers have been used and validated to enable an accurate diagnosis when combined with the clinical history, deferring the oral food challenge, whenever possible. In this review, we cover the tools available to support the diagnosis of food allergies and to predict food allergy resolution over time. We review the latest evidence on different testing modalities and how effective they are in guiding clinical decision-making in practice. We also evaluate predictive test cut-offs for the more common food allergens to try and provide guidance on when challenges might be most successful in determining oral tolerance in children.

Multisystem inflammatory syndrome in children (MIS-C) during the COVID-19 pandemic raised a global alert from the Centers for Disease Control and Prevention’s Health Alert Network. The main manifestations of MIS-C in the setting of a severe inflammatory state include fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes, and in some cases it progressed to multi-organ failure. The low percentage of children with asymptomatic cases compared with mild illness and moderate illness could be correlated with the rare cases of MIS-C. One potential explanation for the progression to severe MIS-C disease despite the presence of readily detectable anti-SARS-CoV-2 antibodies could be due to potential role of antibody-dependent enhancement (ADE). We reason that the incidence of the ADE phenomenon whereby the pathogen-specific antibodies can promote pathology should be considered in vaccine development against SARS-COV-2.

The current pandemic of the novel coronavirus SARS-CoV-2 infection has affected over 6 million humans around the planet. The clinical manifestations of Coronavirus disease 2019 (COVID-19) are diverse, ranging from asymptomatic or mild flu-like symptoms to atypical pneumonia, severe respiratory distress syndrome, systemic inflammation, immune dysregulation and dyscoagulation.Inborn errors of immunity (IEI) are a heterogenous group of more than 430 rare congenital disorders with increased susceptibility to infection, autoimmunity, atopy, hyperinflammation and cancer. Autosomal recessive ARPC1B deficiency is an actinopathy, as are DOCK8 deficiency and the Wiskott-Aldrich Syndrome. Defective actin polymerization affects hematopoietic cells, impairing their migration and immunological synapse1, which results in a combined immune deficiency characterized by leukocytosis, eosinophilia, platelet abnormalities and hypergammaglobulinemia; and clinically, by eczema and food allergy, infections caused by bacteria, fungi and viruses, vasculitis, and bleeding diathesis2.Here, we describe a male infant patient with known ARPC1B deficiency who was hospitalized for COVID-19 pneumonia and improved without requiring intensive care or mechanical ventilation.An 8-month-old infant was brought to the emergency department with high-grade fever. His family history is remarkable for one brother who died as a newborn from intracranial bleeding, and an 11-year-old sister with the same genetic defect who underwent hematopoietic stem-cell transplantation twice without success, and is currently on antimycobacterial treatment, antimicrobial prophylaxis and regular subcutaneous immunoglobulin. The patient was first seen at age 1-month old for eczema and rectal bleeding attributed to cow milk protein allergy. At age 4 months, he developed bronchiolitis caused by respiratory syncytial virus (RSV) and oral candidiasis. Laboratory workup revealed leukocytosis (17,500-33,600/mm3), eosinophilia (5,600-20,100/mm3) and a marginally high (467,000) platelet count; as well as high serum IgG (737 mg/dL) and IgA (165 mg/dL) with normal IgM (37.7 mg/dL). CD8+ T lymphocytes were low at 3% (257 cells) and B cells were elevated at 48% (4,116 cells). Whole exome sequencing identified a homozygous 46 base-pair deletion in exon 8 of ARPC1B(chr7:99,392,784 hg38; p.Glu300fs).Upon his arrival to the emergency department he was febrile with tachycardia and signs of septic shock requiring rapid fluid resuscitation. He showed no respiratory or gastrointestinal signs. He also had a post-traumatic ulcerated lesion under the tongue with dark discoloration, which raised a concern for fungal infection. Intravenous antibiotics (ciprofloxacin) with antifungal coverage were started within the first hour, and a dose of intravenous immunoglobulin (IVIG) at 1g/kg. Blood counts revealed leukocytosis, neutrophilia, and mild eosinophilia without lymphopenia, while platelets were initially found within normal limits. A day later, blood culture had grownPseudomonas aeruginosa .During his second day of hospitalization, the patient persisted febrile, tachycardic and tachypneic, with oxygen desaturation into the low 80s. Chest X-ray showed nonspecific bilateral interstitial opacities in the perihilar regions (Figure 1 ). Real-time Polymerase chain reaction (RT-PCR) for SARS-Cov2 came back positive, and he was then transferred to a COVID-19 isolation area. The potassium hydroxide (KOH) test for oral thrush was negative for yeast cells, after which amphotericin was switched to fluconazole. Supplemental oxygen was discontinued on day 6 of hospitalization, when mild thrombocytopenia and a prolonged thromboplastin time (aPTT) (but normal fibrinogen and ferritin serum levels) were reported. After completing 14 days of antimicrobial treatment, the patient was discharged without ever requiring intensive care unit admission or mechanical ventilation.The behavior of COVID-19 in patients with IEI might help dissect the immune response to SARS-Cov2. A few cases of adults with COVID-19 and predominantly antibody deficiencies have been reported3,4; some of them developed acute respiratory distress syndrome (ARDS), while some had a milder course of illness. Based on what we know, innate immune defects in genes involved in type 1 interferon response (such as IRF7, IRF9, TLR3) are the most likely candidates to result in severe disease and death in patients with flu-like virus infection5. In a few cases of fatal influenza A (H1N1), variants in genes associated with familial hemophagocytic lymphohistiocytosis (FHL) and a decreased cytolytic function of NK cells, were also reported6.Our patient was on monthly supplemental IVIG treatment, and he received an additional dose during his hospital stay. This, and his young age, might have ameliorated the clinical course7. He had a favorable evolution, despite the known susceptibility to viral infection and immune dysregulation in ARPC1B deficient patients1. There were no signs of severe infection, ARDS, hyperinflammation or of “cytokine storm” unleashed by SARS-CoV-2. Despite his having a combined immune deficiency, our patient fully recovered without the need of additional supportive measures other than IVIG, supplemental oxygen and antibiotic treatment directed against the documented bacteremia.Although pediatric cases of COVID-19 are fewer compared to adults, some severe presentations and deaths among children have been reported. The presence of a restricted repertoire of IgG (since infants have no previous exposure to coronaviruses) might play a role in the better outcome seen in pediatric patients. Antibody-dependent enhancement has been implicated in the development of severe COVID-19 in the elderly8. Additionally, lung cells from children and women show a lower expression of membrane-bound ACE-2, which may also be protective against severe pneumonia.Conceivably, some immune defects could protect patients with certain IEIs from mounting a full uncontrolled inflammatory response against SARS-Cov2. The cytoskeleton is a regulator of gene transcription, coupling cell mechanics with the activity of NF-κB. Coronaviruses are thought to alter the cytoskeleton architecture to facilitate viral replication and output9. Thus, ARPC1B deficiency and other actinopathies might limit SARS-CoV-2 replication. Furthermore, Th2 cytokines modulate ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 expression in airway epithelial cells10, and children with allergies (asthma and/or allergic rhinitis) have a lower expression of ACE211. Patients with ARPC1B deficiency often have allergic diseases; their Th2-biased response could help explain the milder presentation seen in our patient. Insights from protective mechanisms in children, with and without certain immune defects, could facilitate the identification of therapeutic targets.Lina Maria Castano-Jaramillo1, MDMarco Antonio Yamazaki-Nakashimada1, MDSelma Cecilia Scheffler Mendoza1, MD, MSJuan Carlos Bustamante-Ogando2, MD, MSSara Elva Espinosa-Padilla2, MD, PhDSaul O. Lugo Reyes2, MD, MS.From the (1) Clinical Immunology Service, and the (2) Immunodeficiencies Research Unit, at the National Institute of Pediatrics, Mexico City, Mexico.Conflict of interests: NoneEthical statement: The patient and his family gave written informed consent for the diagnostic procedures and for publication of the case report.KEY WORDS: Primary immune deficiency, inborn errors of immunity, combined immune deficiency, ARPC1B deficiency, actinopathy, children, COVID-19, SARS-Cov-2, allergy, pneumonia, sepsis.

Background: Exhaled nitric oxide and blood eosinophils are clinical asthma type 2 markers in use. Immunoglobulin E (IgE) is often involved in the inflammation associated with atopic asthma. The effect of both blood eosinophils and allergen-specific IgE on exhaled nitric oxide levels is not completely understood. Twin-design studies can improve understanding of the underlying contribution of genetically and/or environmentally driven inflammation markers in asthma. Our aim was to disentangle the covariance between asthma and exhaled nitric oxide into genetic and environmental contributions that can account for inflammation markers in a paediatric population. Methods: This population-based, cross-sectional twin study enrolled 612 monozygotic (MZ) and same-sex dizygotic (DZ) schoolchildren. Multivariate structural equation modelling was utilized to separate the covariance between asthma and exhaled nitric oxide into genetic and/or environmental effects, taking allergen-specific IgE level and blood eosinophil count into account while controlling for confounding factors. Results: The cross-twin/cross-trait correlations had a higher magnitude in the MZ twins than in the DZ twins indicating that genes affect the association. The likelihood ratio test for model fitting resulted in the AE model as the most parsimonious. A majority, 73%, of the phenotypic correlation between asthma and exhaled nitric oxide, r=0.19 (0.05–0.33), was attributable to genetic effects which mainly was due to the allergen-specific IgE level. Conclusions: This study indicate that the association between asthma - exhaled nitric oxide in children is to a large extent explained by genetics via allergen-specific IgE-level but not blood eosinophils. This might partly explain the clinical heterogeneity in this group. A next step could be to include allergen-specific IgE level in multivariate omic-studies.

Postnatal SARS-CoV-2 Infection and Immunological Reaction: A Prospective Family Cohort Study

Background: Asthmatic children on corticosteroids can develop hypothalamic-pituitary-adrenal axis suppression (HPAS). Single nucleotide polymorphisms (SNPs) rs242941 and rs1876828 of the corticotrophin-releasing hormone receptor 1 (CRHR1) gene were associated with lower stimulated cortisol (F) levels, whereas rs41423247 of the glucocorticoid receptor (NR3C1) gene was associated with higher basal F levels. The objective of the current study was to confirm whether these three SNPs are associated with HPAS in asthmatic children. Methods: DNA was extracted from saliva obtained from 95 asthmatic children, who had previously undergone basal F and metyrapone testing. Thirty-six children were classified as suppressed. Non-suppressed children were sub-classified according to their post-metyrapone ACTH (PMTP ACTH) level into a middle (106-319 pg/ml) and a high (>319 pg/ml) ACTH response group. TaqMan® polymerase chain reaction assays were utilized. Results: Only rs41423247 was inversely associated with HPAS (OR = 0.27 [95% CI 0.06-0.90]). Its GC genotype was inversely associated with HPAS (log odds = - 1.28, p = 0.021). √PMTP ACTH was associated with CC (effect size = 10.85, p = 0.005) and GC genotypes (effect size = 4.06, p = 0.023). The C allele is inherited as a dominant trait (effect size = -1.31 (95% CI -2.39 – -0.33; p = 0.012). In the high ACTH response group, both genotypes affected the PMTP ACTH (effect sizes 1.41 and 15.46; p-values 0.023 and < 2x10-26 for GC and CC respectively). Conclusions: The C allele of rs41423247 was found to be protective against HPAS. CC genotype is associated with the highest PMTP ACTH response.

This review highlights the novelties in understanding the underlying immunological mechanisms of drug hypersensitivity reactions (DHRs) as well as tiny changes in clinical classification and diagnosis of DHRs with special reference to beta-lactams (BLs) in the pediatric population, in the last couple of years. Viral infections are very often in children and they can provoke skin rashes which is difficult to differentiate from DHRs. Because of that allergy to BLs in children is overdiagnosed. The correct diagnosis of BLs allergy in children is still an important and hot topic. In this review has been outlined the need for correct diagnosis of BLs allergy in children as well as needed to change the paradigm.

Comment on Matricardi PM et al.: The first, holistic immunological model of COVID-19: implications for prevention, diagnosis, and public health measuresTO THE EDITOR:We read with great interest the review article by Matricardi and colleagues [1] depicting mechanisms of disease for COVID-19 and analyzing both viral and host factors influencing its course. We particularly agree with Authors on the pivotal role of innate immunity in the very early phase of disease, being crucial for the subsequent evolution. Most known weapons of innate immune system are represented by natural antibodies, non-specific antimicrobial proteins, interferons, cytokines and cellular elements (i.e. natural killer cells).[1] However, innate immunity could be influenced by other, still underrecognized, factors.At present, a solid proof of evidence is available on the ability of vitamin D in modulating immune response.[2] Most of data are available from the field of bacterial infections and sepsis,[3] being low vitamin D levels associated with a higher risk of infection and mortality.[4]In addition, vitamin D could play a role against viruses by maintaining physical barriers (i.e. tight junctions, gap junctions, etc.), enhancing natural immunity (i.e. production of cathelicidin, defensins, etc.) and modulating adaptive immune response (i.e. modulation of TH1/TH2 response and inflammation).[5] On this connection, emerging data support the role of vitamin D supplementation in reducing the risk and severity of influenza.[5] Both influenza and COVID-19 show their maximum spread in winter season and the highest severity in elderly people. Reduced vitamin D levels could represent a possible pathophysiological explanation, among others, in both cases.[5,6] With this regard, it has been hypothesized that variations in vitamin D status across countries and latitudes could, at least in part, explain variations of mortality from COVID-19.[6,7]However, at present the exact vitamin D status among COVID-19 patients is unknown.[7] Moreover, the role and mechanisms of vitamin D in the treatment of COVID-19 are still unexplored and several interventional trials are ongoing. Should these hypotheses be confirmed, universal vitamin D supplementation would represent a possible and inexpensive strategy to enhance natural immunity against COVID-19.Antonio Mirijello, MDMaria Maddalena D’Errico, MDAntonella Lamarca, MDPamela Piscitelli, MDSalvatore De Cosmo, MDDepartment of Medical Sciences, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy